Continuous process for preparing dihydropyrones

ABSTRACT

The invention relates to a continuous process for preparing dihydropyrones of general formula I, 
                         
wherein the groups R 1  and R 2  have the meanings described herein.

RELATED APPLICATIONS DATA

This application claims benefit to German application 10108471.4-44filed Feb. 22, 2001 and U.S. provisional application Ser. No. 60/272,118filed Feb. 28, 2001.

TECHNICAL FIELD OF THE INVENTION

The invention relates to an improved process for preparingdihydropyrones of general formula I,

wherein the groups R¹ and R² may have the meanings given in the detaileddescription hereinbelow.

BACKGROUND TO THE INVENTION

Dihydropyrones are important as intermediate products in drug synthesis.In particular, 5,6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-oneis an important intermediate product in the synthesis of tipranavir, anHIV protease inhibitor. The compounds of formula I and processes forpreparing them are known from the prior art, e.g. from InternationalPatent Application WO 98/19997 and from the “Journal of MedicinalChemistry, 1998, Vol. 41, No. 18”. Recently, a process for preparing aracemic mixture of5,6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one has beendescribed, which comprises in step a) reacting a dianion ofmethylacetoacetate with 1-phenyl-3-hexanone and in a subsequent step b)cyclising the resulting β-ketoester by alkaline hydrolysis followed byacidification. This process is carried out discontinuously and achievesa 72% yield.

The problem of the invention is therefore to provide a process whichenables dihydropyranones to be prepared with a high degree of purity andin a significantly improved yield compared with the prior art.

SUMMARY OF THE INVENTION

It is therefore an object of the invention to provide an improvedprocess for preparing dihydropyrones of general formula I,

wherein the groups R¹ and R² may have the meanings given in the detaileddescription hereinbelow.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that the compounds of formula I can beobtained with a high degree of purity and in a significantly improvedyield if step a) is carried out continuously in a microreactor.

The invention therefore relates to a process, suitable for use in thelaboratory and on an industrial scale, for preparing a compound ofgeneral formula (I),

wherein

-   -   R¹ denotes a C₁–C₈-alkyl, C₆–C₁₀-aryl-C₁–C₄-alkyl or        C₃–C₈-cycloalkyl-C₁–C₄-alkyl group, and    -   R² denotes a C₁–C₈-alkyl group,        -   a) by reacting a ketone of formula (II)

-   -   -   -   wherein R¹and R² are as hereinbefore defined,            -   with an acetoacetate in the presence of a strong base                and

        -   b) by cyclising the resulting compound of formula (IV)

-   -   -   wherein            -   R³ denotes a C₁–C₄-alkyl or benzyl group,            -   wherein the ketone of formula II is continuously reacted                with an acetoacetate in the form of its dianion in a                microreactor.

The microreactors which are suitable for the process according to theinvention are known, for example, from “Microreactors; Wolfgang Ehrfeld,Volker Hessel, Holger Löwe; Wiley-VCH;ISBN 3-527-29590-9; Chapter 3Micromixers”. Microreactors which may be used in the process accordingto the invention generally have a housing made of stainless steel,glass, titanium or metal alloys and an inlay or inlay structures ofthermally oxidised silicon, copper, aluminium, nickel, silver, metalalloys, Foturan glass or metal-coated plastics, glass or ceramicmaterials.

The educt currents may be mixed both turbulently as well as by laminarflow, preferably by laminar flow. The preferred channel structures forlaminar mixing generally include interdigital structures, star-shapedstructures or structures of a worm-type mixer. Types of microreactorwhich may be used for the process according to the invention may beobtained, for example, from the companies Institut für MikrotechnikMainz GmbH, Cellular Process Chemistry GmbH or Mikroglas AG.

Particularly preferred according to the invention is a process wherein amicroreactor with an interdigital channel structure, most preferably amicroreactor of the LIGA type (produced by Lithographie, Galvanoformung,Abformung [lithography, electroforming and moulding]) with aninterdigital channel structure, produced for example by the Institut fürMikrotechnik Mainz GmbH, is used for reaction step a).

Particularly preferred is a process wherein a current of educt Acontaining the compound of formula (II) and a current of educt Bcontaining an acetoacetate in the form of a dianion are continuouslymixed together in the mixing element of a microreactor and the liquidreaction mixture is conveyed into a capillary, particularly a holdingcapillary.

Also particularly preferred is a process wherein the capillary is 0.1 to10 m, preferably 0.3 to 8 m, preferably 0.5 to 6 m, most preferably 0.8to 4 m, particularly preferably about 1 m long and has an internaldiameter of 0.05 to 5 mm, preferably 0.1 to 4 mm, preferably 0.3 to 3mm, particularly preferably about 1 mm.

Particularly preferred is a process wherein 1-phenyl-3-hexanone is usedas the compound of formula (II) in step a).

Also particularly preferred is a process wherein in step a) theacetoacetate is used in the form of a dilithium, monolithium, monosodiumor disodium salt.

Of particular importance is a process wherein the molar ratio of thecompound of formula (III) to the compound of formula (II) used is 2:1 to1:2, preferably 1:1 to 1:1.5, particularly preferably 1:1 to 1:1.2, mostpreferably about 1:1.

Also of particular importance is a process wherein the reaction in stepa) is carried out at a temperature of −78 to +85° C., preferably at −40to +50° C., preferably at −30 to +20° C., more preferably at −25 to+10°C., particularly preferably at −20 to 0° C., most preferably at −15to −5° C., especially preferably at about −10° C.

Also preferred is a process wherein the reaction in step a) is carriedout at an overall flow rate, calculated by adding together the flowrates of the compound of formula II and the acetoacetate, of 1.5 to 5ml/min, preferably at 1.8 to 4 ml/min, particularly preferably at 2 to3.5 ml/min, particularly preferably at about 2.5 ml/min.

Also particularly preferred is a process wherein the flow rate of thecompound of formula (II) to that of the acetoacetate is in a ratio of1:1 to 1:2, preferably 1:1.1 to 1:1.8, particularly preferably 1:1.2 to1:1.5, particularly preferably about 1:1.3.

To achieve these flow rates it is generally advantageous to uselow-vibration pumps, preferably rotary pumps, preferably ceramic rotarypumps or HPLC pumps. The flow rates may be adapted to different types ofreactors to obtain the optimum space/time yield.

Also particularly preferred is a process wherein the reaction is carriedout in a plurality of microreactors connected in series or in parallel.

The 5,6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one obtainedaccording to the invention is preferably used to prepare tipranavir.

In the present invention, the term “alkyl” denotes a straight-chain orbranched alkyl group with 1 to 8 carbon atoms, preferably 2 to 7 carbonatoms, preferably 3 to 6 carbon atoms. Methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec. butyl, tert.butyl, n-pentyl,isopentyl or neopentyl are particularly preferred.

The term “aryl”denotes an aromatic hydrocarbon group with 6 to 10 carbonatoms, preferably phenyl or naphthyl, particularly preferably phenyl,which may be substituted by one or more alkyl groups.

Examples of cycloalkyl groups with 3–8 carbon atoms include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

R¹ is preferably phenylmethyl, phenylethyl or phenylpropyl, mostpreferably 2-phenylethyl, R² is preferably methyl, ethyl, n-propyl orn-butyl, most preferably n-propyl. R³ is preferably methyl, ethyl,n-propyl or benzyl, most preferably ethyl.

Metal hydrides, metal organyls, metal amides, metal dialkylamides ormetal hexamethyldisilazanes are preferably used as strong bases.

Examples of metal cations include lithium, sodium, potassium, rubidium,caesium, magnesium, calcium, titanium, silicon, tin and lanthanoids,preferably lithium or sodium, most preferably lithium.

Particularly preferred bases are sodium hydride, lithium diethylamide,butyl lithium, lithium diisopropylamide, lithium hexamethyl disilazane,sodium hexamethyl disilazane or potassium hexamethyl disilazane orcombinations thereof. As a rule, 2 or more equivalents of these basesare used, preferably 1.8 to 3.0, particularly 1.9 to 2.5 equivalents.The acetoacetate is generally in the form of a dianion of formula III inthe presence of these bases.

The process according to the invention is generally carried out in thepresence of an inert diluent. Preferred diluents are non-polar organicsolvents such as e.g. aliphatic or aromatic hydrocarbons, ethers ormixtures thereof. In a particularly preferred embodiment, the diluent isselected from among dimethoxyethane, diethylether,tert-butyl-methylether, tetrahydrofuran, n-hexane, cyclohexane, toluene,xylene or a mixture of these solvents, particularly tetrahydrofuran anddimethoxyethane.

In addition to the abovementioned diluents the reaction may also containone or more amines such as, for example, diethylamine, diisopropylamineor tetramethylethylenediamine.

The advantage of the process according to the invention is in the highpurity and unexpectedly high yield of dihydropyranone of more than 90%,which results from the continuous microreactor process of step a). Thecompound of formula IV may be further processed as a product of themicroreactor process without further purification.

The following examples serve to illustrate the process according to theinvention still further. They are intended solely as examples ofprocedures without restricting the invention to their content.

EXAMPLE 1 5.6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one

-   Step a)

A mixture I of 81.9 g of 1-phenyl-3-hexanone and 840 ml oftetrahydrofuran and a mixture II of 72.9 g of ethyl-acetoacetate, 117 mlof diethylamine and 450 ml of n-butyllithium in n-hexane (2.5 molar) in361 ml of tetrahydrofuran at −10° C. are pumped towards each other intoa microreactor made by the company Institut für Mikrotechnik Mainz GmbH(of the Liga type with interdigital channel structure) and mixedtogether. The volume flow of mixture I is set to 1 ml/min and the volumeflow of mixture II is set to 1.1 ml/min. The solution of product ispassed through a capillary (length 1 m, diameter 1 mm) and then taken upin saturated ammonium chloride solution/hydrochloric acid solution at apH of 5–6.

-   Step b)

140 g of the crude β-ketoester resulting from step a) are taken up in200 ml of methanol at 5 to 10° C. Solid potassium hydroxide is added at5 to 10° C. with stirring and then the mixture is stirred for about 15hours at ambient temperature. The methanol is distilled off and theresidue is mixed with 500 ml of water. It is extracted twice with 200 mlof toluene. After the organic phase has been separated off, another 400ml of fresh toluene are added to the aqueous phase. This is acidifiedwith conc. sulphuric acid to pH 1.9. The aqueous phase is separated offand the organic phase is extracted 3 times more with water. The organicphase is evaporated to dryness in vacuo (60 mbar) at 40° C. The crudeproduct is dissolved in 200 ml of toluene at 60° C. and then filtered.200 ml of n-octane are slowly added dropwise to the filtrate withstirring at 40° C. It is seeded with5,6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one crystals andstirred for about 15 hours at ambient temperature. 400 ml of n-octaneare added dropwise to the resulting crystal mass which is then cooled to0–5° C. After stirring for about 1 hour at 0–5° C. the crystals aresuction filtered, washed with n-octane and dried. The yield is 92%.

Analogously to Example 1,5,6-dihydro-4-hydroxy-6-phenethyl-6-propyl-2H-pyran-2-one was preparedby carrying out step a) in a microreactor under the conditions specifiedin the following Table:

Volume flow I Yield of (1-phenyl-3- Volume flow II ketoester ExampleTemperature hexanone) (Acetoacetate) [HPLC % No. [° C.] [ml/min][ml/min] area] 2 −25 1 1   84.5 3 −25 1 1.1 87.9 4 −25 1 1.2 83.8 5 −251 1.3 86.4 6 −25 2 2.4 81.1 7 −20 1 1.2 87.2 8 −20 2 2.4 83.8 9 −10 11.2 86.5 10  −10 2 2.4 86.8 11   10 2 2.4 82.1

1. A process for preparing a compound of general formula (I),

wherein R¹ is a C₁–C₈-alkyl, C₆–C₁₀-aryl-C₁–C₄-alkyl orC₃–C₈-cycloalkyl-C₁–C₄-alkyl group, and R² is a C₁–C₈-alkyl group,comprising: reacting a) a ketone of formula (II)

wherein R¹ and R² are as hereinbefore defined, with an acetoacetate inthe presence of a strong base and b) cyclising the resulting compound offormula (IV)

wherein R³ denotes a C₁–C₄-alkyl or benzyl group, by means of a base,wherein a compound of formula II is continuously mixed and reacted withan acetoacetate in the form of its dianion in a microreactor, andsubsequently isolating the product compound of the general formula (I).2. The process according to claim 1, wherein a microreactor with aninterdigital channel structure is used for reaction step a).
 3. Theprocess according to claim 2, wherein a current of educt A containingthe compound of formula (II) and a current of educt B containing theacetoacetate in the form of its dianion are continuously mixed togetherin the mixing element of a microreactor and the liquid reaction mixtureis passed into a holding capillary.
 4. The process according to claim 3,wherein the capillary is 0.1 to 10 m long and 0.05 to 5 mm in diameter.5. The process according to claim 4 wherein 1-phenyl-3-hexanone is usedas the compound of formula (II) in step a).
 6. The process according toclaim 5, wherein step a) the acetoacetate is used in the presence of atleast 2 equivalents of a strong base selected from sodium hydride,butyllithium and lithium dialkylamide.
 7. The process according to claim6, wherein the acetoacetate is added to the compound of formula (II) ina molar ratio of 2:1 to 1:2.
 8. The process according to claim 7 whereinthe reaction in step a) is carried out at a temperature of −78 to +85°C.
 9. The process according to claim 8, wherein the reaction in step a)is carried out at an overall flow rate of 1.5 to 5 ml/min.
 10. Theprocess according to claim 9, wherein the flow rate of the compound offormula (II) to the compound of formula (III) is in a ratio of 1:1 to1:2.
 11. The process according to claim 10 wherein the reaction iscarried out in a plurality of microreactors connected in series or inparallel.